Intravenous iron sucrose versus oral iron administration for the postoperative treatment of post-bariatric abdominoplasty anaemia: an open-label, randomised, superiority trial in Brazil.

BACKGROUND: Anaemia and iron deficiency are common after post-bariatric abdominoplasty, which can involve removal of large areas of skin with associated blood loss. Because the oral absorbability of iron is reduced after bariatric surgery (through reduced intake, reduction of gastric acid secretion for conjugation of iron, and separation of the iron-absorptive areas of the duodenum and jejunum), it has been hypothesised that postoperative intravenous iron supplementation might be used to treat anaemia and iron deficiency in patients submitted to post-bariatric plastic surgeries. We aimed to assess whether intravenous iron administered postoperatively in post-bariatric abdominoplasty could result in increased blood haemoglobin concentrations compared with oral iron supplementation. METHODS: In this open-label, randomised, superiority trial, we recruited women aged 18-55 years undergoing post-bariatric abdominoplasty at two public tertiary referral hospitals in São Paulo, Brazil. Eligible women had been treated for previous obesity with bariatric surgery using the vertical banded gastroplasty technique with Roux-en-Y gastric bypass by laparotomy; had grade III contour deformity via the Pittsburgh rating scale; and had a post-bariatric body-mass index (BMI) lower than 32 kg/m2, with stabilised weight loss for at least 6 months. Women were randomly assigned (1:1) to receive postoperative iron supplementation with two intravenous infusions of 200 mg of iron sucrose (intravenous group) or 100 mg of iron polymaltose complex orally twice a day for 8 weeks (oral group). The primary outcome in both groups was blood haemoglobin concentration at postoperative day 56 after abdominoplasty, with a minimum clinically relevant difference of 1·5 g/dL. Analyses were performed on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01857011, and the Brazilian Clinical Trials Registry, number RBR-2JGRKQ. The trial is completed. FINDINGS: From April 7, 2014, to June 27, 2016, 102 post-bariatric patients were assessed for eligibility. 56 patients were eligible and were randomly assigned, with 28 allocated to each group. Mean baseline haemoglobin concentration was slightly higher in the oral group than in the intravenous group (12·71 g/dL [SD 1·06] vs 12·24 g/L [1·09]), and by post-operative day 56 was 12·54 g/dL (SD 1·18) and 12·80 g/dL (0·81), respectively (mean difference of 0·26 g/dL, 95% CI -0·28 to 0·80; p=0·009 in favour of the intravenous group). The minimum clinically relevant difference in concentrations was not reached. No adverse events were recorded in the intravenous group, whereas in the oral group, constipation was recorded in five (18%) patients, diarrhoea in three (11%), and nausea in one (4%) patient. INTERPRETATION: Postoperative intravenous administration of iron increased haemoglobin concentrations at 56 days post-operatively and reduced iron deficiency, without adverse events. Although superiority of intravenous iron was not shown, intravenous administration might be useful in post-bariatric patients, especially in those who have body-contouring treatment involving a second surgery within a short period of time. Larger trials, and trials using higher intravenous doses of iron, are needed to further assess the potential efficacy and safety of intravenous iron administration after post-bariatric plastic surgery. FUNDING: The São Paulo Research Foundation (FAPESP).

A case of osteomalacia due to deranged mineral balance caused by saccharated ferric oxide and short-bowel syndrome: A case report.

RATIONALE: Saccharated ferric oxide has been shown to lead to elevation of fibroblast growth factor 23, hypophosphatemia, and, consequently, osteomalacia. Moreover, mineral imbalance is often observed in patients with short-bowel syndrome to some degree. PATIENT CONCERNS: A 62-year-old woman with short-bowel syndrome related with multiple resections of small intestines due to Crohn disease received regular intravenous administration of saccharated ferric oxide. Over the course of treatment, she was diagnosed with tetany, which was attributed to hypocalcemia. Additional assessments of the patient revealed not only hypocalcemia, but also hypophosphatemia, hypomagnesemia, osteomalacia, and a high concentration of fibroblast growth factor 23 (314 pg/mL). DIAGNOSES: We diagnosed her with mineral imbalance-induced osteomalacia due to saccharated ferric oxide and short-bowel syndrome. INTERVENTIONS: Magnesium replacement therapy and discontinuation of saccharated ferric oxide alone. OUTCOMES: These treatments were able to normalize her serum mineral levels and increase her bone mineral density. LESSONS: This case suggests that adequate evaluation of serum minerals, including phosphate and magnesium, during saccharated ferric oxide administration may be necessary, especially in patients with short-bowel syndrome.

A randomized trial of iron isomaltoside versus iron sucrose in patients with iron deficiency anemia.

Iron deficiency anemia (IDA) is common in many chronic diseases, and intravenous (IV) iron offers a rapid and efficient iron correction. This trial compared the efficacy and safety of iron isomaltoside (also known as ferric derisomaltose) and iron sucrose in patients with IDA who were intolerant of, or unresponsive to, oral iron. The trial was an open­label, comparative, multi­center trial. Five hundred and eleven patients with IDA from different causes were randomized 2:1 to iron isomaltoside or iron sucrose and followed for 5 weeks. The cumulative dose of iron isomaltoside was based on body weight and hemoglobin (Hb), administered as either a 1000 mg infusion over more than 15 minutes or 500 mg injection over 2 minutes. The cumulative dose of iron sucrose was calculated according to Ganzoni and administered as repeated 200 mg infusions over 30 minutes. The mean cumulative dose of iron isomaltoside was 1640.2 (standard deviation (SD): 357.6) mg and of iron sucrose 1127.9 (SD: 343.3) mg. The primary endpoint was the proportion of patients with a Hb increase ≥2 g/dL from baseline at any time between weeks 1­5. Both non­inferiority and superiority were confirmed for the primary endpoint, and a shorter time to Hb increase ≥2 g/dL was observed with iron isomaltoside. For all biochemical efficacy parameters, faster and/or greater improvements were found with iron isomaltoside. Both treatments were well tolerated; 0.6% experienced a serious adverse drug reaction. Iron isomaltoside was more effective than iron sucrose in achieving a rapid improvement in Hb. Furthermore, iron isomaltoside has an advantage over iron sucrose in allowing higher cumulative dosing in fewer administrations. Both treatments were well tolerated in a broad population with IDA.

AMD-like retinopathy associated with intravenous iron.

Iron accumulation in the retina is associated with the development of age-related macular degeneration (AMD). IV iron is a common method to treat iron deficiency anemia in adults, and its retinal manifestations have not hitherto been identified. To assess whether IV iron formulations can be retina-toxic, we generated a mouse model for iron-induced retinal damage. Male C57BL/6J mice were randomized into groups receiving IV iron-sucrose (+Fe) or 30% sucrose (-Fe). Iron levels in neurosensory retina (NSR), retinal pigment epithelium (RPE), and choroid were assessed using immunofluorescence, quantitative PCR, and the Perls' iron stain. Iron levels were most increased in the RPE and choroid while levels in the NSR did not differ significantly in +Fe mice compared to controls. Eyes from +Fe mice shared histological features with AMD, including Bruch's membrane (BrM) thickening with complement C3 deposition, as well as RPE hypertrophy and vacuolization. This focal degeneration correlated with areas of high choroidal iron levels. Ultrastructural analysis provided further detail of the RPE/photoreceptor outer segment vacuolization and Bruch's membrane thickening. Findings were correlated with a clinical case of a 43-year-old patient who developed numerous retinal drusen, the hallmark of AMD, within 11 months of IV iron therapy. Our results suggest that IV iron therapy may have the potential to induce or exacerbate a form of retinal degeneration. This retinal degeneration shares features with AMD, indicating the need for further study of AMD risk in patients receiving IV iron treatment.

Postoperative intravenously administered iron sucrose versus postoperative orally administered iron to treat post-bariatric abdominoplasty anaemia (ISAPA): the study protocol for a randomised controlled trial.

BACKGROUND: Anaemia and iron deficiency are common complications following post-bariatric abdominoplasty. Given the low oral absorbability of iron resulting from bariatric surgery, it has been hypothesised that postoperative intravenously administered iron supplementation could be used to treat anaemia and to prevent the development of iron deficiency in these patients. METHODS/DESIGN: In this multicentre open-label randomised clinical trial, 56 adult women undergoing post-bariatric anchor-line abdominoplasty will be allocated at a ratio of 1:1 for postoperative supplementation with two intravenously administered applications of 200 mg of iron saccharate or postoperative supplementation with 100 mg of iron polymaltose complex administered orally, twice a day for 8 weeks. The primary outcome is the difference in mean haemoglobin levels between the two groups at eight postoperative weeks. Secondary outcomes evaluated at one, four and eight postoperative weeks include iron profile, reticulocyte count, overall quality of life measured using the Short-Form 36 Health Survey (SF-36) questionnaire, fatigue measured using the Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F), adverse effects and postoperative complications. DISCUSSION: This randomised clinical trial aims to evaluate the haematopoietic effectiveness of intravenously administered iron supplementation in patients undergoing post-bariatric abdominoplasty. A more effective recovery of haemoglobin levels could help improve the patients' quality of life and could provide an improved haematological status in preparation for the subsequent and frequent plastic surgeries these patients undergo. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01857011 (8 May 2013), Universal Trial Number U111-1169-6223, Brazilian Clinical Trials Registry (REBEC): RBR-2JGRKQ .

Randomized controlled trial comparing ferric carboxymaltose and iron sucrose for treatment of iron deficiency anemia due to abnormal uterine bleeding.

OBJECTIVE: To evaluate the efficacy and safety of intravenous ferric carboxymaltose (FCM) in comparison with intravenous iron sucrose (ISC) in the treatment of anemia due to abnormal uterine bleeding (AUB). METHODS: A randomized controlled trial was conducted between April 2013 and May 2014 in patients older than 18 years of age presenting at a hospital in New Delhi, India, with anemia due to AUB. Patients were randomized in a 1:1 ratio to receive treatment with intravenous FCM or ISC. The primary outcome, increase in hemoglobin above baseline, was monitored over a 12-week period. Patients completing the full treatment and follow-up protocol were included in the analyses. Participants and investigators were not masked to treatment allocations. RESULTS: Overall, 30 patients were assigned to each group. Increases in mean hemoglobin levels from baseline were significantly higher in the FCM group at 6 weeks (P=0.005). At 12 weeks, there was no significant difference in hemoglobin increase from baseline between the two groups (P=0.11). Adverse events were similar between both treatment groups. CONCLUSION: Treatment with FCM resulted in a rapid increase in hemoglobin levels in patients with anemia due to AUB, with similar increases in hemoglobin over a 12-week period. Clinical Trial Registration (www.ctri.nic.in):CTRI/2015/09/006224.

Comparative Short-term Safety of Sodium Ferric Gluconate Versus Iron Sucrose in Hemodialysis Patients.

BACKGROUND: Despite different pharmacologic properties, little is known about the comparative safety of sodium ferric gluconate versus iron sucrose in hemodialysis patients. STUDY DESIGN: Retrospective cohort study using the clinical database of a large dialysis provider (2004-2005) merged with administrative data from the US Renal Data System. SETTING & PARTICIPANTS: 66,207 patients with Medicare coverage who received center-based hemodialysis. PREDICTORS: Iron formulation use assessed during repeated 1-month exposure periods (n=278,357). OUTCOMES: All-cause mortality, infection-related hospitalizations and mortality, and cardiovascular-related hospitalizations and mortality occurring during a 3-month follow-up period. MEASUREMENTS: For all outcomes, we estimated 90-day risk differences between the formulations using propensity score weighting of Kaplan-Meier functions, which controlled for a wide range of demographic, clinical, and laboratory variables. Risk differences were also estimated within various clinically important subgroups. RESULTS: Ferric gluconate was administered in 11.4%; iron sucrose, in 48.9%; and no iron in 39.7% of the periods. Risks for most study outcomes did not differ between ferric gluconate and iron sucrose; however, among patients with a hemodialysis catheter, use of ferric gluconate was associated with a slightly decreased risk for both infection-related death (risk difference, -0.3%; 95% CI, -0.5% to 0.0%) and infection-related hospitalization (risk difference, -1.5%; 95% CI, -2.3% to -0.6%). Bolus dosing was associated with an increase in infection-related events among both ferric gluconate and iron sucrose users. LIMITATIONS: Residual confounding and outcome measurement error. CONCLUSIONS: Overall, the 2 iron formulations studied exhibited similar safety profiles; however, ferric gluconate was associated with a slightly decreased risk for infection-related outcomes compared to iron sucrose among patients with a hemodialysis catheter. These associations should be explored further using other data or study designs.

Bullous Skin Lesions in a Patient with End-Stage Renal Disease and Hepatitis C.

Bullous lesions in patients with end-stage renal disease are uncommon and can pose diagnostic and therapeutic challenges. We present a female patient with end-stage renal disease, bullous skin lesions affecting mainly sun-exposed areas, and high ferritin levels. She also had hepatitis C. Her serum porphyrin panel was suggestive of porphyria cutanea tarda. Skin biopsy excluded inflammatory pathologies. Phlebotomy during each hemodialysis, continuation of darbepoetin, and avoidance of any further doses of intravenous iron, with close monitoring of hemoglobin, resulted in a gradual drop in ferritin level and improvement of the skin lesions.

Comparative Risk of Anaphylactic Reactions Associated With Intravenous Iron Products.

IMPORTANCE: All intravenous (IV) iron products are associated with anaphylaxis, but the comparative safety of each product has not been well established. OBJECTIVE: To compare the risk of anaphylaxis among marketed IV iron products. DESIGN, SETTING, AND PARTICIPANTS: Retrospective new user cohort study of IV iron recipients (n = 688,183) enrolled in the US fee-for-service Medicare program from January 2003 to December 2013. Analyses involving ferumoxytol were limited to the period January 2010 to December 2013. EXPOSURES: Administrations of IV iron dextran, gluconate, sucrose, or ferumoxytol as reported in outpatient Medicare claims data. MAIN OUTCOMES AND MEASURES: Anaphylaxis was identified using a prespecified and validated algorithm defined with standard diagnosis and procedure codes and applied to both inpatient and outpatient Medicare claims. The absolute and relative risks of anaphylaxis were estimated, adjusting for imbalances among treatment groups. RESULTS: A total of 274 anaphylaxis cases were identified at first exposure, with an additional 170 incident anaphylaxis cases identified during subsequent IV iron administrations. The risk for anaphylaxis at first exposure was 68 per 100,000 persons for iron dextran (95% CI, 57.8-78.7 per 100,000) and 24 per 100,000 persons for all nondextran IV iron products combined (iron sucrose, gluconate, and ferumoxytol) (95% CI, 20.0-29.5 per 100,000) , with an adjusted odds ratio (OR) of 2.6 (95% CI, 2.0-3.3; P < .001). At first exposure, when compared with iron sucrose, the adjusted OR of anaphylaxis for iron dextran was 3.6 (95% CI, 2.4-5.4); for iron gluconate, 2.0 (95% CI 1.2, 3.5); and for ferumoxytol, 2.2 (95% CI, 1.1-4.3). The estimated cumulative anaphylaxis risk following total iron repletion of 1000 mg administered within a 12-week period was highest with iron dextran (82 per 100,000 persons, 95% CI, 70.5- 93.1) and lowest with iron sucrose (21 per 100,000 persons, 95% CI, 15.3- 26.4). CONCLUSIONS AND RELEVANCE: Among patients in the US Medicare nondialysis population with first exposure to IV iron, the risk of anaphylaxis was highest for iron dextran and lowest for iron sucrose.

[Bone and Nutrition. The relationship between iron and phosphate metabolism].

Fibroblast growth factor 23 (FGF23) is an essential hormone for phosphate metabolism. It has been shown that intravenous administration of some iron formulations including saccharated ferric oxide induces hypophosphatemic osteomalacia with high FGF23 levels. On the other hand, iron deficiency promotes FGF23 and induces hypophosphatemia in patients with autosomal dominant hypophosphatemic rickets (ADHR). While iron and phosphate metabolism is connected, the detailed mechanism of this connection remains to be clarified.

A randomized trial of intravenous and oral iron in chronic kidney disease.

Although iron is commonly used to correct iron deficiency anemia (IDA) in chronic kidney disease (CKD), its effect on kidney function is unclear. To assess this, we randomly assigned patients with stage 3 and 4 CKD and IDA to either open-label oral ferrous sulfate (69 patients to 325 mg three times daily for 8 weeks) or intravenous iron sucrose (67 patients to 200 mg every 2 weeks, total 1 g). The primary outcome was the between-group difference in slope of measured glomerular filtration rate (mGFR) change over two years. The trial was terminated early on the recommendation of an independent data and safety monitoring board based on little chance of finding differences in mGFR slopes, but a higher risk of serious adverse events in the intravenous iron treatment group. mGFR declined similarly over two years in both treatment groups (oral -3.6 ml/min per 1.73 m(2), intravenous -4.0 ml/min per 1.73 m(2), between-group difference -0.35 ml/min per 1.73 m(2); 95% confidence interval -2.9 to 2.3). There were 36 serious cardiovascular events among 19 participants assigned to the oral iron treatment group and 55 events among 17 participants of the intravenous iron group (adjusted incidence rate ratio 2.51 (1.56-4.04)). Infections resulting in hospitalizations had a significant adjusted incidence rate ratio of 2.12 (1.24-3.64). Thus, among non-dialyzed patients with CKD and IDA, intravenous iron therapy is associated with an increased risk of serious adverse events, including those from cardiovascular causes and infectious diseases.

Intravenous Iron Sucrose versus Oral Iron in the Treatment of Pregnancy with Iron Deficiency Anaemia: A Systematic Review.

BACKGROUND: Intravenous iron sucrose and oral iron therapy are the main therapies for iron deficiency anaemia (IDA), but there is still a debate regarding their efficacy and especially as to which one is the best choice during pregnancy. METHODS: A meta-analysis of randomised controlled trials comparing patients treated with intravenous iron sucrose (intravenous group) with those treated with oral iron (oral group) for IDA during pregnancy was performed. The primary outcomes of interest were mean maternal haemoglobin and serum ferritin levels at the end of treatment. Secondary outcomes were treatment-related adverse events and foetal birth weight. RESULTS: Six randomised controlled trials, involving a total of 576 women, were included in the present review. Significant increases in haemoglobin [mean difference (MD), 0.85; 95% confidence interval (CI), 0.31-1.39; p = 0.002] and ferritin levels (MD, 63.32; 95% CI, 39.46-87.18; p < 0.00001) were observed in the intravenous group. Compared with the oral group, there were fewer adverse events in the intravenous group (risk ratio, 0.50; 95% CI, 0.34-0.73; p = 0.0003). There was no significant difference in birth weight between the two groups. CONCLUSION: For pregnant women who could not tolerate the side effects of oral treatment or required a rapid replacement of iron stores, intravenous iron sucrose was associated with fewer adverse events and was more effective than regular oral iron therapy.

Nitrosative Stress and Apoptosis by Intravenous Ferumoxytol, Iron Isomaltoside 1000, Iron Dextran, Iron Sucrose, and Ferric Carboxymaltose in a Nonclinical Model.

Iron is involved in the formation as well as in the scavenging of reactive oxygen and nitrogen species. Thus, iron can induce as well as inhibit both oxidative and nitrosative stress. It also has a key role in reactive oxygen and nitrogen species-mediated apoptosis. We assessed the differences in tyrosine nitration and caspase 3 expression in the liver, heart, and kidneys of rats treated weekly with intravenous ferumoxytol, iron isomaltoside 1000, iron dextran, iron sucrose and ferric carboxymaltose (40 mg iron/kg body weight) for 5 weeks. Nitrotyrosine was quantified in tissue homogenates by Western blotting and the distribution of nitrotyrosine and caspase 3 was assessed in tissue sections by immunohistochemistry. Ferric carboxymaltose and iron sucrose administration did not result in detectable levels of nitrotyrosine or significant levels of caspase 3 vs. control in any of the tissue studied. Nitrotyrosine and caspase 3 levels were significantly (p<0.01) increased in all assessed organs of animals treated with iron dextran and iron isomaltoside 1000, as well as in the liver and kidneys of ferumoxytol-treated animals compared to isotonic saline solution (control). Nitrotyrosine and caspase 3 levels were shown to correlate positively with the amount of Prussian blue-detectable iron(III) deposits in iron dextran- and iron isomaltoside 1000-treated rats but not in ferumoxytol-treated rats, suggesting that iron dextran, iron isomaltoside 1000 and ferumoxytol induce nitrosative (and oxidative) stress as well as apoptosis via different mechanism(s).

A Phase III, randomized, open-label trial of ferumoxytol compared with iron sucrose for the treatment of iron deficiency anemia in patients with a history of unsatisfactory oral iron therapy.

Iron deficiency anemia (IDA) is the most common form of anemia worldwide. Although oral iron is used as first-line treatment, many patients are unresponsive to or cannot take oral iron. This Phase III, open-label, non-inferiority study compared the efficacy and safety of ferumoxytol, a rapid, injectable intravenous (IV) iron product with low immunological reactivity and minimal detectable free iron, with IV iron sucrose in adults with IDA of any cause. Patients (N = 605) were randomized 2:1 to receive ferumoxytol (n = 406, two doses of 510 mg 5 ± 3 days apart) or iron sucrose (n = 199, five doses of 200 mg on five nonconsecutive days over 14 days) and followed for 5 weeks. Ferumoxytol demonstrated noninferiority to iron sucrose at the primary endpoint, the proportion of patients achieving a hemoglobin increase of ≥2 g dL(-1) at any time from Baseline to Week 5 (ferumoxytol, 84.0% [n = 406] vs. iron sucrose, 81.4% [n = 199]), with a noninferiority margin of 15%. Ferumoxytol was superior to iron sucrose (2.7 g dL(-1) vs. 2.4 g dL(-1) ) in the mean change in hemoglobin from Baseline to Week 5 (the alternative preplanned primary endpoint) with P = 0.0124. Transferrin saturation, quality-of-life measures, and safety outcomes were similar between the two treatment groups. Overall, ferumoxytol demonstrated comparable safety and efficacy to iron sucrose, suggesting that ferumoxytol may be a useful treatment option for patients with IDA in whom oral iron was unsatisfactory or could not be used.

A randomized comparison of ferumoxytol and iron sucrose for treating iron deficiency anemia in patients with CKD.

BACKGROUND AND OBJECTIVES: Few randomized controlled trials have compared intravenous iron products head to head in CKD patients with iron deficiency anemia. This study compared the efficacy and safety of two intravenous iron products (ferumoxytol [Feraheme injection] and iron sucrose [Venofer]) in patients with CKD and iron deficiency anemia. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this phase II, randomized, open-label, active-controlled, multicenter clinical trial, patients were randomized 1:1 to either 1.02 g ferumoxytol (2 × 510-mg injections) or 1.0 g iron sucrose administered as either a slow injection or infusion (10 doses for dialysis patients and 5 doses for nondialysis patients). Inclusion criteria included hemoglobin<11.0 g/dl, transferrin saturation<30%, and eGFR<60 ml/min per 1.73 m(2) or a diagnosis of underlying CKD (e.g., nephropathy or nephritis). The primary end point was change in hemoglobin from baseline to week 5. RESULTS: In total, 162 patients were randomized. Demographics were balanced between the treatment groups. Adverse event profiles of the two regimens were fairly similar: overall adverse events, 48% ferumoxytol versus 65% iron sucrose; related adverse events, 10% ferumoxytol versus 16% iron sucrose; and adverse events leading to study discontinuation, 1% ferumoxytol versus 5% iron sucrose. Rates of serious adverse events and related serious adverse events were similar between the ferumoxytol and iron sucrose groups: serious adverse events, 9% versus 7%, respectively and related serious adverse events, 1% versus 1%, respectively. Overall, increases in hemoglobin were similar between treatment groups. Based on an ANOVA model adjusted for baseline hemoglobin level and dialysis status, the least squares mean change from baseline to week 5 was 0.8 ± 0.1 g/dl in the ferumoxytol-treated group and 0.7 ± 0.1 g/dl in the iron sucrose group. The difference in the mean change from baseline between the two treatment groups was 0.1 g/dl (95% confidence interval, -0.2 to 0.4). CONCLUSION: In this randomized, controlled trial, ferumoxytol and iron sucrose showed comparable efficacy and adverse events rates.